Has the rescheduling of modified-release paracetamol in Australia affected the frequency of overdoses?

OBJECTIVES: In June 2020, modified-release paracetamol (paracetamol-MR) preparations were up-scheduled from schedule-2 (available in pharmacy) to schedule-3 (available by request to a pharmacist only). The present study aims to ascertain whether up-scheduling affected the frequency of paracetamol-MR overdoses. METHODS: This is a retrospective cohort study of two data sets from 1 June 2017 to 31 May 2022. Monash Health data were extracted using the diagnosis of paracetamol overdose coding and electronic medical records data. Calls regarding paracetamol-MR overdoses to Victorian Poisons Information Centre (VPIC) were extracted from the Poisons centre call database. We used a quasi-experimental research design with interrupted time series analysis to evaluate the immediate impact and change in trend of poisoning-related calls and ED presentations before and after June 2020. The change in proportion of paracetamol-MR cases in both databases was analysed using the Χ2 test. RESULTS: The proportion of paracetamol-MR cases in both data sets did not change. From Monash Health, there was no level change in monthly paracetamol-MR overdose-related presentations following re-scheduling (rate ratio [RR] = 1.08, 95% confidence interval [CI] = 0.57-2.01). There was no change in monthly paracetamol-MR overdose-related calls to VPIC following re-scheduling (RR = 1.05, 95% CI = 0.96-1.14). CONCLUSION: The proportion of paracetamol-MR overdoses did not decrease after the up-scheduling to S3. Similarly, the frequency of overdoses by month remained similar. Further limitations on access to paracetamol products may need to be considered.

Analysis of guideline recommendations for treatment of asthma exacerbations in children: a Pediatric Emergency Research Networks (PERN) study.

RATIONALE: There is significant practice variation in acute paediatric asthma, particularly severe exacerbations. It is unknown whether this is due to differences in clinical guidelines. OBJECTIVES: To describe and compare the content and quality of clinical guidelines for the management of acute exacerbations of asthma in children between geographic regions. METHODS: Observational study of guidelines for the management of acute paediatric asthma from institutions across a global collaboration of six regional paediatric emergency research networks. MEASUREMENTS AND MAIN RESULTS: 158 guidelines were identified. Half provided recommendations for at least two age groups, and most guidelines provided treatment recommendations according to asthma severity.There were consistent recommendations for the use of inhaled short-acting beta-agonists and systemic corticosteroids. Inhaled anticholinergic therapy was recommended in most guidelines for severe and critical asthma, but there were inconsistent recommendations for its use in mild and moderate exacerbations. Other inhaled therapies such as helium-oxygen mixture (Heliox) and nebulised magnesium were inconsistently recommended for severe and critical illness.Parenteral bronchodilator therapy and epinephrine were mostly reserved for severe and critical asthma, with intravenous magnesium most recommended. There were regional differences in the use of other parenteral bronchodilators, particularly aminophylline.Guideline quality assessment identified high ratings for clarity of presentation, scope and purpose, but low ratings for stakeholder involvement, rigour of development, applicability and editorial independence. CONCLUSIONS: Current guidelines for the management of acute paediatric asthma exacerbations have substantial deficits in important quality domains and provide limited and inconsistent guidance for severe exacerbations.

Core outcomes and factors influencing the experience of care for children with severe acute exacerbations of asthma: a qualitative study.

OBJECTIVE: To identify the outcomes considered important, and factors influencing the patient experience, for parents and caregivers of children presenting to hospital with a severe acute exacerbation of asthma. This work contributes to the outcome-identification process in developing a core outcome set (COS) for future clinical trials in children with severe acute asthma. DESIGN: A qualitative study involving semistructured interviews with parents and caregivers of children who presented to hospital with a severe acute exacerbation of asthma. SETTING: Hospitals in 12 countries associated with the global Pediatric Emergency Research Networks, including high-income and middle-income countries. Interviews were conducted face-to-face, by teleconference/video-call, or by phone. FINDINGS: Overall, there were 54 interviews with parents and caregivers; 2 interviews also involved the child. Hospital length of stay, intensive care unit or high-dependency unit (HDU) admission, and treatment costs were highlighted as important outcomes influencing the patient and family experience. Other potential clinical trial outcomes included work of breathing, speed of recovery and side effects. In addition, the patient and family experience was impacted by decision-making leading up to seeking hospital care, transit to hospital, waiting times and the use of intravenous treatment. Satisfaction of care was related to communication with clinicians and frequent reassessment. CONCLUSIONS: This study provides insight into the outcomes that parents and caregivers believe to be the most important to be considered in the process of developing a COS for the treatment of acute severe exacerbations of asthma.

Characteristics and time course of benzodiazepine-type new psychoactive substance detections in Australia: results from the Emerging Drugs Network of Australia - Victoria project 2020-2022.

INTRODUCTION: The emergence of benzodiazepine-type new psychoactive substances (NPSs) are a growing international public health concern, with increasing detections in drug seizures and clinical and coronial casework. This study describes the patterns and nature of benzodiazepine-type NPS detections extracted from the Emerging Drugs Network of Australia - Victoria (EDNAV) project, to better characterise benzodiazepine-type NPS exposures within an Australian context. METHODS: EDNAV is a state-wide illicit drug toxicosurveillance project collecting data from patients presenting to an emergency department with illicit drug-related toxicity. Patient blood samples were screened for illicit, pharmaceutical and NPSs utilising liquid chromatography-tandem mass spectrometry. Demographic, clinical, and analytical data was extracted from the centralised registry for cases with an analytical confirmation of a benzodiazepine-type NPS(s) between September 2020-August 2022. RESULTS: A benzodiazepine-type NPS was detected in 16.5 % of the EDNAV cohort (n = 183/1112). Benzodiazepine-type NPS positive patients were predominately male (69.4 %, n = 127), with a median age of 24 (range 16-68) years. Twelve different benzodiazepine-type NPSs were detected over the two-year period, most commonly clonazolam (n = 82, 44.8 %), etizolam (n = 62, 33.9 %), clobromazolam (n = 43, 23.5 %), flualprazolam (n = 42, 23.0 %), and phenazepam (n = 31, 16.9 %). Two or more benzodiazepine-type NPSs were detected in 47.0 % of benzodiazepine-type NPS positive patients. No patient referenced the use of a benzodiazepine-type NPS by name or reported the possibility of heterogenous product content. CONCLUSION: Non-prescription benzodiazepine use may be an emerging concern in Australia, particularly amongst young males. The large variety of benzodiazepine-type NPS combinations suggest that consumers may not be aware of product heterogeneity upon purchase or use. Continued monitoring efforts are paramount to inform harm reduction opportunities.

Acute paediatric asthma treatment in the prehospital setting: a retrospective observational study.

OBJECTIVES: To describe the incidence of and patterns of 'escalated care' (care in addition to standard treatment with systemic corticosteroids and inhaled bronchodilators) for children receiving prehospital treatment for asthma. DESIGN: Retrospective observational study. SETTING: State-wide ambulance service data (Ambulance Victoria in Victoria, Australia, population 6.5 million) PARTICIPANTS: Children aged 1-17 years and given a final diagnosis of asthma by the treating paramedics and/or treated with inhaled bronchodilators from 1 July 2019 to 30 June 2020. PRIMARY AND SECONDARY OUTCOME MEASURES: We classified 'escalation of care' as parenteral administration of epinephrine, or provision of respiratory support. We compared clinical, demographic and treatments administered between those receiving and not receiving escalation of care. RESULTS: Paramedics attended 1572 children with acute exacerbations of asthma during the 1 year study period. Of these, 22 (1.4%) had escalated care, all receiving parenteral epinephrine. Patients with escalated care were more likely to be older, had previously required hospital admission for asthma and had severe respiratory distress at initial assessment.Of 1307 children with respiratory status data available, at arrival to hospital, the respiratory status of children had improved overall (normal/mild respiratory distress at initial assessment 847 (64.8%), normal/mild respiratory distress at hospital arrival 1142 (87.4%), p<0.0001). CONCLUSIONS: Most children with acute exacerbations of asthma did not receive escalated therapy during their pre-hospital treatment from ambulance paramedics. Most patients were treated with inhaled bronchodilators only and clinically improved by the time they arrived in hospital.

Intravenous Lipid Emulsion does NOT have a role in severe poisoning: CON.

Intravenous lipid emulsion (ILE) has been suggested as a potential universal antidote for cardiovascular and central nervous system toxicity resulting from a multitude of pharmaceutical and nonpharmaceutical poisonings. While there is some evidence to suggest that ILE may have a positive effect in cardiovascular system toxicity after accidental intravenous lipophilic local anaesthetic overdose, this cannot be extrapolated to cases of severe poisoning resulting from oral drug overdose. Treatment recommendations are based upon variable outcome animal studies and low-level clinical evidence with a significant degree of positive reporting bias. Currently, there is a paucity of controlled clinical data to support ILE use to treat severe drug poisoning after oral overdose. ILE use should be limited to well-designed, ethically approved, controlled clinical trials aimed at determining the true effectiveness of this therapy. This should replace the current scattergun clinical use in a multiplicity of poisoning scenarios and subsequent anecdotal reporting approach.

Non-fatal intoxications involving the novel benzodiazepine clonazolam: case series from the Emerging Drugs Network of Australia - Victoria project.

INTRODUCTION: Clonazolam is an unregistered novel benzodiazepine which emerged in global illicit drug markets in 2014. We describe the clinical features of four cases of non-fatal clonazolam mono-intoxications from patients presenting to emergency departments in Australia. CASES: Four patients aged between 16 and 19 years presented to hospital with a sedative toxidrome (Glasgow Coma Scale range 8-13) and elevated heart rate (median heart rate 100 beats per minute, range 92-105) following reported benzodiazepine exposure. Three patients reported the use of a large quantity (7-20 tablets) of Xanax®, a brand of alprazolam not commercially available in Australia. Two patients required nasopharyngeal airway insertion following the development of airway obstruction. The median time to return of a normal conscious state (Glasgow Coma Scale 15) was 23 h (range 5-30 h). Clonazolam (range 0.2-2.1 µg/L) and its main metabolite 8-aminoclonazolam (range 5.9-19.1 µg/L) were the only substances detected by liquid chromatography-tandem mass spectrometry in blood samples of all patients. CONCLUSION: Clonazolam intoxication resulted in sedation with mild sinus tachycardia. Three patients who reported multiple tablet exposures experienced prolonged sedation, and two of these patients developed airway obstruction. In this series, clonazolam was unknowingly ingested through possible illicit substitution within an unregulated counterfeit benzodiazepine product.

Evolution in the choice of therapies used to treat latrodectism: Redback spider antivenom or standard analgesic medications. Nothing to rave about.

OBJECTIVES: Redback spider (RBS) antivenom (RBSAV) use appears to have decreased since the results of the RAVE-2 antivenom efficacy study were released. The aims of this study were to assess change in RBSAV use over time and compare responses to treatment for antivenom and other analgesics. METHODS: Retrospective audit of RBS bite referrals to a toxicology unit, from January 2010 to January 2022. Data included demographics, pain severity, treatment (analgesia or RBSAV), response to treatment, re-presentation rate, adverse events, change in antivenom use over time. RESULTS: Of 270 presentations, 157 with moderate or severe pain were included (RBSAV n = 51, analgesia n = 106). Median age was 39 years, n = 81 (51%) female. Those receiving antivenom were more likely to report severe pain n = 46/51 (84%) versus n = 68/106 (58%) (P = 0.006). Eighty-three percent of antivenom doses were administered between 2010 and 2013. Analgesia-only group received various combinations of paracetamol, NSAIDs, and opioids. In those receiving RBSAV, 17/48 (35%), 26/48 (54%), 5/48 (10%) reported a partial, complete or no reduction in pain, respectively, versus 30/77 (39%), 43/77 (58%) and 4/77 (5%), for analgesia-only group. Post-treatment pain was not recorded in three RBSAV and 28 analgesia-only patients. Pain reduction was no different for intravenous and intramuscular antivenom. Re-presentation for ongoing pain was more common in the analgesia-only group, 16/106 (15%) versus 1/51 (2%) for antivenom (P = 0.013). CONCLUSION: Antivenom use fell over the study period. There was no difference in pain relief between RBSAV and analgesia-only groups. RBSAV, regardless of route of administration, was no better than standard analgesics in pain reduction in the present study.

From signal to alert: A cluster of exposures to counterfeit alprazolam tablets containing five novel benzodiazepines.

OBJECTIVE: To illustrate the toxicosurveillance role of the Emerging Drugs Network of Australia - Victoria (EDNAV) project in informing timely harm minimisation interventions. METHODS: Utilisation of an ethics approved clinical registry storing de-identified clinical and analytical data on Victorian ED illicit drug-related presentations. RESULTS: In April 2022, six adults presented to hospital with varying levels of sedation, following the use of counterfeit benzodiazepines. Comprehensive toxicological analysis identified five separate novel benzodiazepines within blood samples from each patient. A public 'Drug Alert' was subsequently issued, and local emergency physicians were notified. CONCLUSION: Toxicosurveillance projects, such as EDNAV, are critical to the continued monitoring and reporting of illicit substance use in the community.

Changes in ionized calcium in ethylene glycol poisoning.

Ethylene glycol is a sweet-tasting toxic alcohol contained in a variety of chemical preparations. In patients poisoned with ethylene glycol, diagnosis is often based upon clinical suspicion and nonspecific tests. Hypocalcemia is often present due to calcium oxalate crystals formed by oxalic acid metabolite complexation. This retrospective study involved a review of clinical records of patients with a diagnosis of ethylene glycol poisoning. Results of blood gas samples, lactate, ionized calcium, and serum creatinine were documented and compared between various groups. The ionized calcium concentration was below the normal range in 59% of cases at the time of presentation and more commonly associated with a blood pH of <7.3 in 79% of cases. The number of patients with a low ionized calcium concentration increased over time. A low ionized calcium concentration was a common finding in cases of severe ethylene glycol poisoning and was more commonly associated with patients exhibiting metabolic acidosis or developing acute kidney injury or death. Ionized calcium concentration on presentation may be an additional marker in concert with blood pH that can be used in the risk assessment and stratification of severity and complications of ethylene glycol poisoning.

Validation of a nomogram used to predict lithium concentration in overdose.

INTRODUCTION: Extracorporeal Treatment (ECTR) is an essential component in management of severe lithium toxicity. The Extracorporeal Treatments in Poisoning (EXTRIP) group's suggested indications for ECTR include "if the expected time to obtain a [Li+] < 1.0mEq/L with optimal management is >36h". Buckley et al. developed a lithium nomogram which could help predict the fall in lithium concentrations for chronic poisoning. Our aim is to externally validate the lithium nomogram in a cohort of cases with chronic accumulation and acute on chronic lithium poisoning. METHODS: A retrospective analysis of suspected cases of chronic accumulation and acute on chronic lithium poisoning referred to our Toxicology Unit from May 2013 to 2020 was performed. RESULTS: Out of 51 cases, 29 cases of chronic accumulation and eight cases of acute on chronic poisoning were analysed after excluding 14 cases who required haemodialysis. In chronic accumulation cases, the nomogram correctly identified 10 out of 14 patients whose [Li+] failed to drop below 1.0 mmol/L by 36 h (sensitivity 71.4% [95% CI 42 - 92%]), and 8 out of 15 patients whose [Li+] dropped below 1.0 mmol/L by 36 h (specificity 53.3% [95% CI 27 - 78%]), resulting in the positive predictive value (PPV) of 58.8%, negative predictive value (NPV) of 66.7% and accuracy of 62.1%. CONCLUSIONS: Our study shows that the lithium nomogram is moderately sensitive at identifying patients with chronic lithium accumulation who will have a serum lithium concentration >1 mmol/L at 36 h without ECTR.

Treatment patterns and frequency of key outcomes in acute severe asthma in children: a Paediatric Research in Emergency Departments International Collaborative (PREDICT) multicentre cohort study.

RATIONALE: Severe acute paediatric asthma may require treatment escalation beyond systemic corticosteroids, inhaled bronchodilators and low-flow oxygen. Current large asthma datasets report parenteral therapy only. OBJECTIVES: To identify the use and type of escalation of treatment in children presenting to hospital with acute severe asthma. METHODS: Retrospective cohort study of children with an emergency department diagnosis of asthma or wheeze at 18 Australian and New Zealand hospitals. The main outcomes were use and type of escalation treatment (defined as any of intensive care unit admission, nebulised magnesium, respiratory support or parenteral bronchodilator treatment) and hospital length of stay (LOS). MEASUREMENTS AND MAIN RESULTS: Of 14 029 children (median age 3 (IQR 1-3) years; 62.9% male), 1020 (7.3%, 95% CI 6.9% to 7.7%) had treatment escalation. Children with treatment escalation had a longer LOS (44.2 hours, IQR 27.3-63.2 hours) than children without escalation 6.7 hours, IQR 3.5-16.3 hours; p<0.001). The most common treatment escalations were respiratory support alone (400; 2.9%, 95% CI 2.6% to 3.1%), parenteral bronchodilator treatment alone (380; 2.7%, 95% CI 2.5% to 3.0%) and both respiratory support and parenteral bronchodilator treatment (209; 1.5%, 95% CI 1.3% to 1.7%). Respiratory support was predominantly nasal high-flow therapy (99.0%). The most common intravenous medication regimens were: magnesium alone (50.4%), magnesium and aminophylline (24.6%) and magnesium and salbutamol (10.0%). CONCLUSIONS: Overall, 7.3% children with acute severe asthma received some form of escalated treatment, with 4.2% receiving parenteral bronchodilators and 4.3% respiratory support. There is wide variation treatment escalation.

Comparing development of liver injury using the two versus three bag acetylcysteine regimen despite early treatment in paracetamol overdose.

INTRODUCTION: Some studies have reported that early administration of acetylcysteine using a 3-bag regimen may not fully prevent development of liver injury in some patients. We compared the incidence of acute liver injury (ALI) in patients receiving acetylcysteine within eight hours of ingestion between the two-bag acetylcysteine regimen (200 mg/kg over four hours, 100 mg/kg over 16 h) and the three-bag regimen (150 mg/kg over 1 h, 50 mg/kg over 4 h, 100 mg/kg over 16 h). METHOD: This was a retrospective cohort study of the two-bag and three-bag acetylcysteine regimens from Monash Health, Victoria, Australia (2009-2020), compared to the three-bag acetylcysteine regimen data from the Canadian Acetaminophen Overdose Study (CAOS) database (1980-2005). The inclusion criteria included patients with an acute single ingestion of paracetamol; normal aminotransferases on presentation and acetylcysteine administered within eight hours post-overdose. The primary outcome was development of ALI (defined as: peak aminotransferase >150 IU/L). RESULTS: At Monash Health, 191 patients were treated with the two-bag acetylcysteine regimen, and 180 patients with the three-bag regimen. The CAOS cohort provided 515 patients treated with the three-bag regimen. ALI developed in 1.6% (3/191) of the two-bag Monash Health group, 2.2% (4/180) of the three-bag Monash Health group (difference -0.6%, p 0.7), and 2.9% (15/515) of the three-bag CAOS group (difference compared to two-bag -1.3%, p 0.4). Hepatotoxicity (ALT >1000) developed in 0.5% (1/191) of patients treated with the two-bag regimen, 1.7% (3/180) in the Monash Health three-bag regimen and 1% (5/515) of the three-bag CAOS group. There were no statistically significant differences between groups. CONCLUSIONS: ALI and hepatotoxicity were observed in a small, comparable percentage of patients despite early acetylcysteine administration using the two-bag and three-bag regimens. Repeating blood tests at the end of acetylcysteine treatment will identify these patients and indicate those requiring continuation of acetylcysteine.

A two-bag acetylcysteine regimen is associated with shorter delays and interruptions in the treatment of paracetamol overdose.

BACKGROUND: The three-bag intravenous (IV) acetylcysteine regimen for paracetamol overdose is associated with frequent and long delays during treatment. This has not been previously studied in regard to the two-bag regimen. AIMS: Our primary aim was to compare the cumulative duration of delays during IV acetylcysteine infusion between the three-bag and two-bag regimens. Secondary aims were to compare the frequency of delays and to identify causes for delay. METHODS: This was a retrospective cohort study of patients receiving IV acetylcysteine for the treatment of paracetamol overdose, conducted at three Australian emergency departments. A cohort of patients treated with the three-bag regimen from October 2009 to October 2013 was compared to patients treated with the two-bag regimen from February 2014 to May 2020. Start times of each infusion were sourced from medical records and delays were calculated by comparing actual infusion time against prescribed time. Evidence of adverse drug reactions - gastrointestinal reactions and cutaneous and systemic non-allergic anaphylactoid reactions (NAARs) - were also recorded. RESULTS: The three-bag cohort included 271 cases and the two-bag cohort included 598 cases. Delays were significantly shorter in the two-bag cohort, compared to the three-bag cohort: median delay 35 min (IQR: 15, 70) vs 65 min (IQR: 40, 105), p < 0.01. Delays longer than 1 h were less frequent in the two-bag cohort: 31% vs 51%, p < 0.01. NAARs were associated with significantly longer delays in both cohorts and were more frequent in the three-bag cohort. CONCLUSIONS: The two-bag regimen was associated with significantly fewer and shorter delays. NAARs, which were more frequent in the three-bag cohort, were associated with significantly longer delays.

Characteristics, presentation and outcomes of music festival patrons with stimulant drug-induced serotonin toxicity.

OBJECTIVE: A large number of stimulant drug-associated deaths at music festivals in Australia were reported during the southern hemisphere summer of 2018-2019. This led to the prehospital deployment of healthcare professional-led critical care response teams. We aimed to describe the characteristics, clinical presentation, management and outcomes of music festival patrons with stimulant drug-induced serotonin toxicity managed using this model during the study period. METHODS: We performed a retrospective observational study of patients presenting with stimulant drug-induced serotonin toxicity and/or drug-induced hyperthermia who presented between December 2017 and December 2019. Comprehensive follow-up data were collected for those patients who required hospital admission. Data included demographics, clinical features, management and disposition, hospital outcomes and laboratory data, stratified by severity of presentation. RESULTS: Forty-seven patients were included. Median age was 21.9 years (interquartile range 19.6-22.2). 3,4-Methylenedioxymetamphetamine was the most frequently reported agent ingested (32/47). After stratification, 13 of 47 patients were classified as mild, 20 of 47 as moderate and 14 of 47 as severe. Median presenting temperature in this latter cohort was 41.1°C (40.5-42.0°C). All severely ill patients required intensive care unit admission, with a median hospital stay of 4.63 days (interquartile range 2.08-8.36). End-organ complications were reported in 11 of 14 patients. No mortalities were reported. All patients (13/13) from the mild cohort and 15 of 20 patients from the moderate cohort were treated and discharged on-site. CONCLUSIONS: Severe illness was associated with a high incidence of end-organ impairment. A high proportion of patients without severe disease were able to be successfully managed at the event without transport to hospital. No deaths are reported in this series.

Comparing propofol with placebo for early resolution of acute migraine in adult emergency department patients: A double-blind randomised controlled trial.

OBJECTIVE: To compare propofol with placebo in adult ED patients with acute migraine. Primary outcome was headache resolution by 1 h. Secondary outcome was reduction in headache severity by two or more points on a numerical rating scale. METHODS: Double-blind randomised controlled clinical trial comparing propofol (10 mg/mL) with placebo (20% intralipid). Adults with acute migraine without aura were included. The study drug was administered as an initial dose of 4 mL followed by up to five doses of 2 mL, delivered 5 min apart. Pain scores were taken prior to each dose and further administration was ceased when either the pain score was zero or the maximum dosage reached (140 mg of propofol or 14 mL of 20% intralipid). RESULTS: Of 40 recruited patients, 21 received propofol and 19 placebo. Headache resolution occurred for 5 (24%, 95% CI 13-57) and 6 (32%, 95% CI 13-57) patients, respectively, difference 8% (95% CI -20 to 36). Headache severity reduction by two or more numerical rating scale points was reported by 17 (81%, 95% CI 58-95) and 7 (37%, 95% CI 16-62) patients, respectively, difference 44% (95% CI 17-71). CONCLUSIONS: Propofol was not superior to placebo for the primary outcome of early headache resolution. Superiority of propofol for the secondary outcome of headache severity reduction suggests that further research may be warranted.